1. Field of the Invention
This invention concerns newly synthesized glucocorticoids and their local use both as topically active anti-inflammatory agents and as inhalant anti-inflammatory agents for the control of asthma.
2. Description of Prior Art
The adrenal glands continuously produce glucocorticoids. These compounds give rise to a range of critical regulatory functions in the body. Over the past thirty years researchers have synthesized a variety of glucocorticoid analogs and have administered these synthetic analogs as well as the natural materials to treat a variety of conditions. For example, they have been administered systemically or locally as aerosol inhalants to treat asthma that does not respond to other forms of treatment; to treat muscle inflammation; and they have been injected into inflamed muscles and connective tissues to reduce local inflammation. In these systemic applications, there is a serious side reaction. That is, as the glucocorticoids are administered, a feedback signal is delivered to the adrenals which shuts down their production of glucocorticoid material. This effect is referred to in the literature as "adrenal suppression". When the administered dose is withdrawn, there is a substantial lag period before the adrenals receive a signal from the brain to begin production anew. The body is left without an adequate supply of glucocorticoids. This can lead to shock, coma and death.
The glucocorticoids have also been used as topical agents. They have been used to treat psoriasis and other proliferative skin diseases, poison oak, poison ivy and like allergenic responses, atopic dermatitis, diaper rash and the like. In these applications, the corticoid is applied as a cream or lotion. With glucocoticoids used heretofore, these topical applications can present the same adrenal suppression difficulties. When large areas of skin are involved in the treatment, or the treatment is continued over long periods of time, the prior materials are absorbed through the skin to levels which can lead to systemic reactions such as adrenal suppression. Similarly, when repeated inhalation doses are desired with prior materials, systemic reactions become an issue and limit the amount of material which can be safely administered.
The present invention provides a family of new glucocorticoids which have excellent topical activity but which do not appear to give rise to systemic side effects on the order of those previously observed. Although not understood with certainty, it is proposed by the inventor herein that this effect is either the result of uniquely superior topical activity or the result of unexpectedly favorable partitioning of topical and systemic activity. Thus, the compounds of this invention are topically useful for dermatological conditions and as inhalants (such as replacements for beclomethasone dipropionate) for the control of asthma.
As will be appreciated, a vast number of steroidal analogs have been disclosed in the literature. A number of these are now commerical products such as prednisone, cortisone, betamethasone, beclomethasone, dexamethasone, the 17,21-dipropionate of the latter three, and the like. The present materials include a beta substituent at the steroid C-12 position. Others have substituted the C-12 position in the past, using different techniques and inserting different substituents from those of the present invention. See, for example, U.S. Pat. No. 4,198,336; U.S. Pat. No. 4,086,254; U.S. Pat. No. 3,934,013; M. J. Green, et al., J Chem Soc Chem Comm (1977), 611; D. H. R. Barton, et al., J Chem Soc (Perkin 1) (1973), 2365; D. Taub, et al., J Am Chem Soc, Vol. 79, 452; E. M. Chamberlin, et al., J Am Chem Soc, Vol 79, 456; J. E. Herz, et al., J Am Chem Soc, Vol 78, 2017; D. Taub, et al., J Am Chem Soc, Vol 78, 2912; P. A. Diassi, et al., J Am Chem Soc, Vol 83, 4249; M. Wolff, Burger's Medicinal Chemistry, Part III, 4th Ed., Manfred E. Wolff (Wiley-Interscience, 1981), at pp. 1308-09.